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Abundance of A beta(5-x) x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2014 (English)In: Molecular Neurodegeneration, ISSN 1750-1326, Vol. 9, 13- p.Article in journal (Refereed) Published
Abstract [en]

Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (A beta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated A beta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that A beta(x-42) isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and A beta(x-42) species have been pointed as crucial players in AD etiology, the A beta(5-x) isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of A beta(5-x) in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe A beta(5-x) peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of A beta(5-x) distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular A beta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal A beta(5-x). Conclusions: Different degrees of A beta(5-x) accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular A beta(5-x), these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher A beta(5-x)-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving A beta(5-x) peptides and operating in a divergent way in the late and early onset forms of the disease.

Place, publisher, year, edition, pages
2014. Vol. 9, 13- p.
Keyword [en]
A beta(5-x), Amyloid plaques, 5XFAD, 3xTG, APP/PS1KI, Vascular deposits, N-truncated A beta
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URN: urn:nbn:se:uu:diva-225064DOI: 10.1186/1750-1326-9-13ISI: 000334719400001OAI: diva2:728025
Available from: 2014-06-23 Created: 2014-05-27 Last updated: 2014-06-23Bibliographically approved

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Lannfelt, LarsIngelsson, Martin
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